2,2-Difluoro-16-phenoxy-13,14 dihydro-PGE, analogs

ABSTRACT

2,2-Difluoro prostaglandin E, F.sub.α, F.sub.β, A, and B analog are disclosed with intermediates and with processes for making them. These compounds differ from the prostaglandins in that they have two fluoro atoms at the C-2 position in place of the two hydrogen atoms at C-2 in the prostaglandins. These compounds are useful for a variety of pharmacological purposes, including antiulcer, inhibition of platelet aggregation, increase in nasal patency, labor induction at term, and wound healing.

The present application is a divisional application of Ser. No. 552,708, filed Feb. 24, 1975, now issued as U.S. Pat. 4,001,300, on Jan. 4, 1977.

The present invention relates to prostaglandin analogs for which the essential material constituting a disclosure therefor is incorporated by reference here from U.S. Pat. 4,001,300, issued Jan. 4, 1977. 

I claim:
 1. A compound of the formula ##STR1## OR A MIXTURE COMPRISING THAT COMPOUND AND THE ENANTIOMER THEREOF, WHEREIN G IS 2 TO 4, INCLUSIVE;Wherein M₁ is ##STR2## wherein R₇ and R₈ are hydrogen or methyl, with the proviso that one of R₇ or R₈ is methyl only when the other is hydrogen; Wherein T is alkyl of one to 3 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₄ wherein R₄ is alkyl of one to 3 carbon atoms, inclusive, and wherein s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl; Wherein R₁ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro, alkyl of one to 4 carbon atoms, inclusive, or a pharmacologically acceptable cation, ##STR3## WHEREIN R₅ is hydrogen or methyl, with the proviso that R₅ is methyl only when R₇ and R₈ are both hydrogen.
 2. A compound according to claim 1, wherein M₁ is ##STR4##
 3. A compound according to claim 2, wherein g is
 2. 4. A compound according to claim 3, wherein s is 0 or s is one and T is chloro, fluoro, or trifluoromethyl.
 5. A compound according to claim 4, wherein R₇ is methyl.
 6. A compound according to claim 5, wherein s is 1 and T is trifluoromethyl.
 7. 2,2-Difluoro-15-methyl-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, a compound according to claim 6, wherein R₁ is hydrogen.
 8. 2,2-Difluoro-15-methyl-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, methyl ester, a compound according to claim 6, wherein R₁ is methyl.
 9. A compound according to claim 5, wherein s is 1 and T is fluoro.
 10. 2,2-Difluoro-15-methyl-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, a compound according to claim 9, wherein R₁ is hydrogen.
 11. 2,2-Difluoro-15-methyl-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE.sub.1 methyl ester, a compound according to claim 9, wherein R₁ is methyl.
 12. A compound according to claim 5, wherein s is one and T is chloro.
 13. 2,2-Difluoro-15-methyl-16-(p-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, a compound according to claim 12, wherein R₁ is hydrogen.
 14. 2,2-Difluoro-15-methyl-16-(p-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE.sub.1, methyl ester, a compound according to claim 12, wherein R₁ is methyl.
 15. A compound according to claim 5, wherein s is
 0. 16. 2,2-Difluoro-15-methyl-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGE₁, a compound according to claim 15, wherein R₁ is hydrogen.
 17. 2,2-Difluoro-15-methyl-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGE₁, methyl ester, a compound according to claim 15, wherein R₁ is methyl.
 18. A compound according to claim 4, wherein R₈ is methyl.
 19. A compound according to claim 18, wherein s is one, and T is trifluoromethyl.
 20. 2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, 15-methyl ether, a compound according to claim 19, wherein R₁ is hydrogen.
 21. 2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, 15-methyl ether, methyl ester, a compound according to claim 19, wherein R₁ is methyl.
 22. A compound according to claim 18, wherein T is fluoro.
 23. 2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, 15-methyl ether, a compound according to claim 22, wherein R₁ is hydrogen.
 24. 2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, 15-methyl ether, methyl ester, a compound according to claim 22, wherein R₁ is methyl.
 25. A compound according to claim 18, wherein s is one and T is chloro.
 26. 2,2-Difluoro-16-(p-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, 15-methyl ether, methyl ester, a compound according to claim 25, wherein R₁ is hydrogen.
 27. 2,2-Difluoro-16-(p-chlorophenoxy)-17,18,19,20-tetra-13,14-dihydro-PGE₁, 15-methyl ether, methyl ester, a compound according to claim 25, wherein R₁ is methyl.
 28. A compound according to claim 18, wherein s is
 0. 29. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGE₁, 15-methyl ether, a compound according to claim 28, wherein R₁ is hydrogen.
 30. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGE₁, 15-methyl ether, methyl ester, a compound according to claim 28, wherein R₁ is methyl.
 31. A compound according to claim 4, wherein R₇ and R₈ are hydrogen.
 32. A compound according to claim 31, wherein R₅ is methyl.
 33. A compound according to claim 32, wherein s is one and T is trifluoromethyl.
 34. 2,2-Difluoro-16methyl-16-(m-trifluoromethylphenoxy)-18,19,20-trinor-13,14-dihydro-PGE.sub.1, a compound according to claim 33, wherein R₁ is hydrogen.
 35. 2.2-Difluoro-16-methyl-16-(m-trifluoromethylphenoxy)-18,19,20-trinor-13,14-dihydro-PGE₁, methyl ester, a compound according to claim 33, wherein R₁ is methyl.
 36. A compound according to claim 32, wherein s is one and T is fluoro.
 37. 2,2-Difluoro-16-(p-fluorophenoxy)-18,19,20-trinor-13,14-dihydro-PGE.sub.1, a compound according to claim 36, wherein R₁ is hydrogen.
 38. 2,2-Difluoro-16-methyl-16-(p-fluorophenoxy)-18,19,20-trinor-13,14-dihydro-PGE₁, methyl ester, a compound according to claim 36, wherein R₁ is methyl.
 39. A compound according to claim 32, wherein s is one and T is chloro.
 40. 2,2-Difluoro-16-methyl-16-(p-chlorophenoxy)-18,19,20-trinor-13,14-dihydro-PGE₁, a compound according to claim 39, wherein R₁ is hydrogen.
 41. 2,2-Difluoro-16-methyl-16-(p-chlorophenoxy)-18,19,20-trinor-13,14-dihydro-PGE₁, methyl ester, a compound according to claim 39, wherein R₁ is methyl.
 42. A compound according to claim 32, wherein s is
 0. 43. 2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-PGE₁, methyl ester, a compound according to claim 42, wherein R₁ is methyl.
 44. 2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-PGE₁, methyl ester, a compound according to claim 42, wherein R₁ is methyl.
 45. A compound according to claim 31, wherein R₅ is hydrogen.
 46. A compound according to claim 45, wherein s is one and T is trifluoromethyl.
 47. 2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, a compound according to claim 46, wherein R₁ is hydrogen.
 48. 2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, methyl ester, a compound according to claim 46, wherein R₁ is methyl.
 49. A compound according to claim 45, wherein s is one and T is fluoro.
 50. 2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetra-13,14-dihydro-PGE.sub.1, a compound according to claim 49, wherein R₁ is hydrogen.
 51. 2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, methyl ester, a compound according to claim 49, wherein R₁ is methyl.
 52. A compound according to claim 45, wherein s is one and T is chloro.
 53. 2,2-Difluoro-16-(p-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, a compound according to claim 52, wherein R₁ is hydrogen.
 54. 2,2-Difluoro-16-(p-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGE₁, methyl ester, a compound according to claim 52, wherein R₁ is methyl.
 55. A compound according to claim 45, wherein s is
 0. 56. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGE₁, a compound according to claim 55, wherein R₁ is hydrogen.
 57. 2.2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGE₁, methyl ester, a compound according to claim 55, wherein R₁ is methyl.
 58. The compound according to claim 1, wherein M₁ is ##STR5## 